243 APC = activated recombinant protein C; IL = interleukin; PAF = platelet-activating factor; TNF = tumor necrosis factor. Available online http://ccforum.com/content/9/3/243 Abstract Acute pancreatitis results from a sequence of events that involve the systemic inflammatory response. Activated C has multiple anti- inflammatory activities and may attenuate the degree of pancreatic injury and systemic organ dysfunction when infused early in pancreatitis Acute pancreatitis results from a sequence of pathologic events that involves the systemic inflammatory response [1,2]. The initial event is activation and retention of digestive enzymes in the acinar cells, with subsequent cellular injury. In addition, the acinar cells release inflammatory mediators, which leads to recruitment of neutrophils, formation of free radicals, and activation of the complement system. The neutrophils and macrophages generate additional cytokines, nitric oxide, platelet-activating factor (PAF), and other sub- stances. The amplified inflammatory response exacerbates the pancreatic injury, causing evolution from an edematous to a necrotic pancreas. Spillage of the inflammatory mediators into the systemic circulation produces organ failure. The importance of the inflammatory cascade in this process is evidenced by the correlation of serum IL-6 with disease severity in acute pancreatitis [3]. Multiple experimental studies have examined the role of therapies directed at modulating the inflammatory response in acute pancreatitis. The hypothesis is that interventions, applied early in the course of pancreatitis, can attenuate the severity of pancreatic injury and the associated systemic organ dysfunction. Agents directed at tumor necrosis factor (TNF), IL-1, nuclear factor-κB, inhibitors of lipid peroxidation, and PAF are among those that have been demonstrated to reduce the severity of pancreatic injury in experimental models [1]. The PAF antagonist lexipafant has also been studied in clinical pancreatitis. However, in a large multicenter trial [4] administration of lexipafant did not result in a significant decrease in mortality or in the severity of the pancreatitis. Activated recombinant protein C (APC), a derivative of a naturally occurring anticoagulant, reduces mortality in severe sepsis [5]. In addition to its anticoagulant and profibrinolytic properties, APC appears to modulate the inflammatory response through multiple other mechanisms [6,7]. It has direct effects on neutrophil integrin expression and neutrophil–endothelial cell interactions. Inhibition of nuclear factor-κB activation, TNF release, and induction of nitric oxide synthetase have also been demonstrated. In addition, APC also appears to have an antiapoptotic effect. These observations have led to the utilization of APC in other syndromes in which inflammation and neutrophil mediated injury play central roles, such as reperfusion, and spinal cord and radiation injury. A study by Yamanel and coworkers [8], presented in this issue of Critical Care, examines the role played by APC in reducing pancreatic injury in a taurocharate induced model of acute pancreatitis. APC given 6 hours after the induction of pancreatitis significantly reduced acinar necrosis, tissue edema, fat necrosis, and inflammatory infiltration compared with controls. However, tissue hemorrhage scores were not different between groups. These changes were associated with a reduction in serum TNF, IL-6, and amylase levels. These results suggest that APC may reduce the inflammatory process associated with pancreatitis. As is the case with severe sepsis, it is difficult to determine which mechanisms of action play the primary role in ameliorating tissue injury in this model. The observation that hemorrhage scores were not reduced, in concert with the other pathologic findings, is a matter of concern. The authors interpretation is that this finding suggests an ‘intact coagulation system’. An alternative perspective is that, in the presence of decreases in all other parameters of histologic injury, the lack of a parallel change in the hemorrhage score indicates an increased bleeding risk associated with APC. The relative importance of this Commentary Acute pancreatitis: a possible role for activated protein C? Linda Kirschenbaum and Mark Astiz Saint Vincents Hospital, New York, New York, USA Corresponding author: Mark E Astiz, meastiz@aol.com Published online: 13 April 2005 Critical Care 2005, 9:243-244 (DOI 10.1186/cc3515) This article is online at http://ccforum.com/content/9/3/243 © 2005 BioMed Central Ltd See related research by Yamanel et al. in this issue [http://ccforum.com/content/9/3/R184] 244 Critical Care June 2005 Vol 9 No 3 Kirschenbaum and Astiz complication is not clear, given the lower systemic cytokine and amylase levels in the APC treated animals. One element missing in the study is a histopathologic score at 6 hours before the administration of APC. Whether APC attenuates the progression from edematous pancreatitis to necrotizing pancreatitis, or whether it limits the severity of established necrotizing pancreatitis has important clinical implications. Indeed, one explanation for the therapeutic failure of the PAF antagonist lexipafant is that it might have been administered too late in the clinical course to be of benefit. The development of a secondary infection in necrotic pancreatic tissue is an important complication that contributes to morbidity and mortality in acute pancreatitis [9]. Translocation of enteric bacteria from the intestine is postulated to play an important role in the development of this complication. In the study by Yamanel and coworkers [8], APC was also found to reduce significantly the incidence of culture positive mesenteric lymph nodes and pancreatic tissue. The authors suggested that this may be related to APC induced downregulation in inducible nitric oxide synthase activity. However, the role of nitric oxide in bacterial translocation in pancreatitis is controversial. Others have suggested that nitric oxide substrates may reduce bacterial translocation by preserving microvascular blood flow [10]. To the extent that this mechanism is important in maintaining the integrity of the intestinal barrier, the benefit observed with APC may have been related to its effects in reducing leukocyte–endothelial cell interactions, thereby improving the intestinal microcirculation [11]. The data from the study by Yamanel and coworkers [8] are preliminary and require confirmation in other models of pancreatitis. It would also seem important to determine whether the benefit of APC, if any, in experimental acute pancreatitis occurs before or after the development of acute necrotizing pancreatitis. As currently approved, whether in the USA or Europe, APC is utilized for established severe sepsis with complications. In contrast, the study presented in this issue, as well as much of the experimental work in this area, represents an effort to intervene early in pancreatitis in order to reduce the progression to severe necrotizing pancreatitis, with its attendant complications [1,12]. The concept of utilizing APC prophylactically in a clinical syndrome represents a new and intriguing application of this agent. Competing interests LK and MA receive research funding from Eli Lilly. References 1. Bhatia M, Brady M, Shokuhi S, Christmas S, Neoptolemos JP, Slavin J: Inflammatory mediators in acute pancreatitis. J Pathol 2000, 190:117-125. 2. Norman J: The role of cytokines in the pathogenesis of acute pancreatitis. Am J Surg 1998, 175:76-83. 3. Frossard J, Hadengue A, Pastor C: New serum markers for the detection of severe acute pancreatitis in humans. Am J Respir Crit Care Med 2001, 164:162-170. 4. Nathens AB, Curtis JR, Beale RJ, Cook DJ, Moreno RP, Romand JA, Skerrett SJ, Stapleton RD, Ware LB, Waldmann CS: Manage- ment of the critically ill patient with severe acute pancreatitis. Crit Care Med 2004, 32:2254-2536. 5. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, et al.: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001, 344:699-709. 6. Esmon C: Protein C pathway. Chest 2003, 1224:26S-32S. 7. Van de Wouwer M, Collen D, Conway E: Thrombomdulin- protein C-EPCR system: integrated to regulate coagulation and inflammation. Arterioscler Thromb Vasc Biol 2004, 24: 1374-1383. 8. Yamanel L, Mas RM, Comert B, Isik TA, Aydin S, Mas NN, Deveci S, Ozyurt M, Tasci I, Unal T: The effect of activated protein C on experimental acute necrotizing pancreatitis. Crit Care 2005, 9: R184-R190. 9. Beger H, Bittner R, Block S, Buchler M: Bacterial contamination of pancreatic necrosis. A prospective clinical study. Gastroen- terology 1986, 91:433-438. 10. Cevikel MH, Ozgun H, Boylu S, Demirkiran AE, Sakarya S, Culhaci N: Nitric oxide regulates bacterial translocation in experimental acute pancreatitis. Pancreatology 2003, 3:329- 335. 11. Iba T, Kidokoro A, Fukunaga M, Nagakari K, Shirahama A, Ida Y: Activated protein C improves the visceral microcirculation by attenuating leukocyte-endothelial interaction in a rat lipopoly- saccharide model. Crit Care Med 2005, 33:368-372. 12. Frossard JL, Morel P, Pastor C: Why clinical trials might succeed in acute pancreatitis when they failed in septic shock. J Pancreas 2003, 4:11-16. . oxide regulates bacterial translocation in experimental acute pancreatitis. Pancreatology 2003, 3:329- 335. 11. Iba T, Kidokoro A, Fukunaga M, Nagakari K, Shirahama A, Ida Y: Activated protein. this Commentary Acute pancreatitis: a possible role for activated protein C? Linda Kirschenbaum and Mark Astiz Saint Vincents Hospital, New York, New York, USA Corresponding author: Mark E Astiz, meastiz@aol.com Published. nuclear factor-κB activation, TNF release, and induction of nitric oxide synthetase have also been demonstrated. In addition, APC also appears to have an antiapoptotic effect. These observations